Neuronal NLRP3 is a parkin substrate that drives neurodegeneration in Parkinson's disease.

Parkinson's disease (PD) is mediated, in part, by intraneuronal accumulation of α-synuclein aggregates andsubsequent death of dopamine (DA) neurons in the substantia nigra pars compacta (SNpc). Microglial hyperactivation of the NOD-like receptor protein 3 (NLRP3) inflammasome has been well-documented in various neurodegenerative diseases, including PD. We show here that loss of parkin activity in mouse and human DA neurons results in spontaneous neuronal NLRP3 inflammasome assembly, leading to DA neuron death. Parkin normally inhibits inflammasome priming by ubiquitinating and targeting NLRP3 for proteasomal degradation. Loss of parkin activity also contributes to the assembly of an active NLRP3 inflammasome complex via mitochondrial-derived reactive oxygen species (mitoROS) generation through the accumulation of another parkin ubiquitination substrate, ZNF746/PARIS. Inhibition of neuronal NLRP3 inflammasome assembly prevents degeneration of DA neurons in familial and sporadic PD models. Strategies aimed at limiting neuronal NLRP3 inflammasome activation hold promise as a disease-modifying therapy for PD.

• Publication year

  2022

• Venue

  Neuron

• Publication date

  2022-05-25

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1016/j.neuron.2022.05.009PMID 35654037PMCID PMC9357148
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Mitochondrial-derived damage-associated molecular patterns amplify neuroinflammation in neurodegenerative diseases

  2022cited by this paper
• STING mediates neurodegeneration and neuroinflammation in nigrostriatal α-synucleinopathy

  2022cited by this paper
• Deubiquitinase CYLD acts as a negative regulator of dopamine neuron survival in Parkinson’s disease

  2022cited by this paper
• Parkinson Disease: Translating Insights from Molecular Mechanisms to Neuroprotection

  2021cited by this paper
• TRIP12 ubiquitination of glucocerebrosidase contributes to neurodegeneration in Parkinson's disease.

  2021cited by this paper
• PARIS farnesylation prevents neurodegeneration in models of Parkinson’s disease

  2021cited by this paper
• Defects in Mitochondrial Biogenesis Drive Mitochondrial Alterations in PARKIN-Deficient Human Dopamine Neurons

  2020cited by this paper
• PARIS induced defects in mitochondrial biogenesis drive dopamine neuron loss under conditions of parkin or PINK1 deficiency

  2020cited by this paper
• PINK1 and Parkin mitochondrial quality control: a source of regional vulnerability in Parkinson’s disease

  2020cited by this paper
• AIM2 inflammasome surveillance of DNA damage shapes neurodevelopment

  2020cited by this paper
• Slc6a3-dependent expression of a CAPS-associated Nlrp3 allele results in progressive behavioral abnormalities and neuroinflammation in aging mice

  2020cited by this paper
• The NLRP3 inflammasome: molecular activation and regulation to therapeutics

  2019cited by this paper
• Mitochondrial damage by α-synuclein causes cell death in human dopaminergic neurons

  2019cited by this paper
• α-Synuclein pathology spread through the brain connectome is modulated by selective vulnerability and predicted by network analysis

  2019cited by this paper
• Parkin interacting substrate zinc finger protein 746 is a pathological mediator in Parkinson's disease.

  2019cited by this paper
• Fyn kinase regulates misfolded α-synuclein uptake and NLRP3 inflammasome activation in microglia

  2019cited by this paper
• Poly(ADP-ribose) drives pathologic α-synuclein neurodegeneration in Parkinson’s disease

  2018cited by this paper
• Parkin deficiency modulates NLRP3 inflammasome activation by attenuating an A20‐dependent negative feedback loop

  2018cited by this paper
• NLRP3 expression in mesencephalic neurons and characterization of a rare NLRP3 polymorphism associated with decreased risk of Parkinson’s disease

  2018cited by this paper
• Inflammasome inhibition prevents α-synuclein pathology and dopaminergic neurodegeneration in mice

  2018cited by this paper
• PINK1 Primes Parkin-Mediated Ubiquitination of PARIS in Dopaminergic Neuronal Survival.

  2017cited by this paper
• Caspase-1 causes truncation and aggregation of the Parkinson’s disease-associated protein α-synuclein

  2016cited by this paper
• α-Synuclein binds to TOM20 and inhibits mitochondrial protein import in Parkinson’s disease

  2016cited by this paper
• Pathological α-synuclein transmission initiated by binding lymphocyte-activation gene 3

  2016cited by this paper
• Parkin loss leads to PARIS-dependent declines in mitochondrial mass and respiration

  2015cited by this paper
• NLRP3 activation and mitosis are mutually exclusive events coordinated by NEK7, a new inflammasome component

  2015cited by this paper
• Mitochondrial Dysfunction in Parkinson's Disease

  2015cited by this paper
• Improved vectors and genome-wide libraries for CRISPR screening

  2014cited by this paper
• PINK1 phosphorylates ubiquitin to activate Parkin E3 ubiquitin ligase activity

  2014cited by this paper
• Parkin and PINK1: much more than mitophagy.

  2014cited by this paper
• Mechanisms and functions of inflammasomes.

  2014cited by this paper
• Structure of the human Parkin ligase domain in an autoinhibited state

  2013cited by this paper
• Recognition of bacteria by inflammasomes.

  2013cited by this paper
• Mitochondrial dysfunction in Parkinson's disease: molecular mechanisms and pathophysiological consequences

  2012cited by this paper
• Pathological α-Synuclein Transmission Initiates Parkinson-like Neurodegeneration in Nontransgenic Mice

  2012cited by this paper
• NLRP3 is activated in Alzheimer´s disease and contributes to pathology in APP/PS1 mice

  2012cited by this paper
• Floor plate-derived dopamine neurons from hESCs efficiently engraft in animal models of PD

  2011cited by this paper
• Discovery of catalytically active orthologues of the Parkinson's disease kinase PINK1: analysis of substrate specificity and impact of mutations

  2011cited by this paper
• PARIS (ZNF746) repression of PGC-1α contributes to neurodegeneration in Parkinson's disease.

  2011cited by this paper
• A role for mitochondria in NLRP3 inflammasome activation

  2011cited by this paper
• Inflammasome-mediated disease animal models reveal roles for innate but not adaptive immunity.

  2009cited by this paper
• Diagnosis and treatment of Parkinson disease: molecules to medicine.

  2006cited by this paper
• Distinct Roles of TLR2 and the Adaptor ASC in IL-1β/IL-18 Secretion in Response to Listeria monocytogenes1

  2006cited by this paper
• Parkinson's Disease Mechanisms and Models

  2003cited by this paper
• Mitochondrial formation of reactive oxygen species

  2003cited by this paper
• The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta.

  2002cited by this paper
• Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism

  1998cited by this paper

• Artificial intelligence and multi-omics nominate TAZ as an insomnia-related diagnostic and druggable target for Parkinson's disease patients.

  2026cites this paper
• VPA targets Mid1 improves hippocampal neurons retrograde axonal transport function disruption in lithium manganate-induced mice learning and memory dysfunction through the ubiquitin-proteasome pathway.

  2026cites this paper
• Zinc-α₂-glycoprotein overexpression attenuates gasdermin D-mediated pyroptosis in dopaminergic neurons by suppressing reactive oxygen species/mitogen-activated protein kinase signaling.

  2026cites this paper
• Brain fog in Parkinson’s disease: unraveling mechanisms and measuring impact

  2026cites this paper
• Targeting microglial inflammation in Parkinson’s disease: irisin activates PAFAH1B1-RAGE ubiquitination and TFEB-dependent autophagy to alleviate neurodegeneration

  2026cites this paper
• Mitophagy–NLRP3 Inflammasome Crosstalk in Parkinson’s Disease: Pathogenic Mechanisms and Emerging Therapeutic Strategies

  2026cites this paper
• TGFβ1 attenuates microglial IL1β release through inhibition of NLRP3 inflammasome priming

  2026cites this paper
• Organelle stress in NLRP3 inflammasome: a central mediator of neurodegenerative diseases

  2026cites this paper
• NLRP3 facilitates α-synuclein-induced dopaminergic neuronal senescence in a mouse model of Parkinson's disease through SATB1/DNA damage/p21 signaling pathway.

  2026cites this paper
• Parkin Deficiency Impairs ER-Mitochondria Associations and calcium homeostasis via IP3R-Grp75-VDAC1 Complex

  2026cites this paper
• Exosomes Regulate the NLRP3/Caspase-1/IL-1β Signaling Pathway in Parkinson's Disease: Mechanisms of Neuroinflammation Modulation and α-Synuclein Propagation.

  2026cites this paper
• The parkin-γ-tubulin axis regulates epidermal homeostasis and is associated with the susceptibility to psoriasis.

  2026cites this paper
• PARK7-Nrf2 axis mitigates NLRP3-driven inflammation to rescue neurovascular unit from hypoxia/reoxygenation-induced necroptosis.

  2026cites this paper
• Esculin Alleviated NLRP3 Inflammasome Activation by Inducing PINK1/Parkin-Mediated Mitophagy in Cerebral Ischemia–Reperfusion Injury

  2026cites this paper
• Cordycepin promotes autophagic degradation of α-synuclein via CacyBP/SIP activation for ameliorating olfactory dysfunction against Parkinson's disease.

  2025cites this paper
• Immune Cell Proteins and Parkinson's Disease: A Mendelian Randomization Analysis of Causal Associations

  2025cites this paper
• Antiageing strategy for neurodegenerative diseases: from mechanisms to clinical advances

  2025cites this paper
• JC124 confers multimodal neuroprotection in epilepsy by suppressing NLRP3 inflammasome activation: evidence from animal and human neuronal models

  2025cites this paper
• The role of NLRP3 inflammasome in necrotizing enterocolitis

  2025cites this paper
• Lactobacillus reuteri-derived γ-amino butyric acid alleviates MPTP-induced Parkinson’s disease through inhibiting ferroptosis via the AKT-GSK3β-GPX4 axis

  2025cites this paper
• An update on the involvement of inflammatory mediators in Parkinson’s disease pathogenesis

  2025cites this paper
• Electroacupuncture alleviates Parkinson's disease by inhibiting the NLRP3 inflammasome pathway.

  2025cites this paper
• Inhibition of α-synuclein aggregation by MCC950 attenuates dopaminergic neuronal damage in MN9D cells.

  2025cites this paper
• Rebamipide (Mucosta®), a clinically approved drug, alleviates neuroinflammation and dopaminergic neurodegeneration in a Parkinson’s disease model

  2025cites this paper
• Targeting inflammasome pathway towards therapeutics of neurodegenerative diseases

  2025cites this paper
• Advances in research on mitochondrial dysfunction in neurodegenerative diseases

  2025cites this paper
• MiR-223-3p inhibits hippocampal neurons injury and exerts anti- anxiety/depression-like behaviors by directly targeting NLRP3

  2025cites this paper
• Nanozymes: Innovative Therapeutics in the Battle Against Neurodegenerative Diseases

  2025cites this paper
• Aerobic Exercise Restores Hippocampal Neurogenesis and Cognitive Function by Decreasing Microglia Inflammasome Formation Through Irisin/NLRP3 Pathway

  2025cites this paper
• Bilirubin Targeting WNK1 to Alleviate NLRP3‐Mediated Neuroinflammation

  2025cites this paper
• New Insights on the Potential Role of Pyroptosis in Parkinson’s Neuropathology and Therapeutic Targeting of NLRP3 Inflammasome with Recent Advances in Nanoparticle-Based miRNA Therapeutics

  2025cites this paper
• NLRP3 inflammasome in neuroinflammation and central nervous system diseases

  2025cites this paper
• Current trends in blood biomarkers detection and neuroimaging for Parkinson's disease.

  2025cites this paper
• Protective Effects of Mdivi‐1 on Cognition Disturbance Following Sepsis in Mice via Alleviating Microglia Activation and Polarization

  2025cites this paper
• Neurogenic inflammation and itch in barrier tissues.

  2025cites this paper
• Recent advances in research on common targets of neurological and sex hormonal influences on asthma

  2025cites this paper
• Genistein-3'-sodium sulfonate suppresses NLRP3-mediated cell pyroptosis after cerebral ischemia

  2025cites this paper
• Targeting the NLRP3 inflammasome in Parkinson's disease: From molecular mechanism to therapeutic strategy.

  2025cites this paper
• NLRX1 limits inflammatory neurodegeneration in the anterior visual pathway

  2025cites this paper
• Strategic Mutations in Designer Native Peptides Combat NLRP3 Inflammasome Activation in Neurodegenerative Disorders.

  2025cites this paper
• Canonical and noncanonical autophagy: involvement in Parkinson’s disease

  2025cites this paper
• Mitochondrial Dynamics in Neurodegenerative Diseases: Research Hotspots and Trends from 2005 to 2025.

  2025cites this paper
• Short-Chain Fatty Acid Aggregates Alpha-Synuclein Accumulation and Neuroinflammation via GPR43-NLRP3 Signaling Pathway in a Model Parkinson’s Disease

  2025cites this paper
• Porphyromonas gingivalis and Its Outer Membrane Vesicles Induce Neuroinflammation in Mice Through Distinct Mechanisms

  2025cites this paper
• Detection of hypochlorous acid fluctuation via a near-infrared fluorescent probe in Parkinson's disease cells and mouse models.

  2025cites this paper
• Zika virus inhibits cell death by inhibiting the expression of NLRP3 and A20

  2025cites this paper
• Neuronal guidance signaling in neurodegenerative diseases: Key regulators that function at neuron-glia and neuroimmune interfaces

  2025cites this paper
• Inactivation of NLRP3 inflammasome by dephosphorylation at Serine 658 alleviates glial inflammation in the mouse model of Parkinson’s disease

  2025cites this paper
• Mechanisms and therapeutic strategies for NLRP3 degradation via post-translational modifications in ubiquitin-proteasome and autophagy lysosomal pathway.

  2025cites this paper
• Dendrobium huoshanense Attenuates Parkinsonian Neurodegeneration via Dual Antioxidant and Anti-inflammatory Pathways.

  2025cites this paper
• Didymin Alleviates Neuropathic Pain by Targeting RKIP-Mediated NF-κB/NLRP3 Crosstalk to Inhibit Pyroptosis and Neuroinflammation.

  2025cites this paper
• Neuronal inflammasomes: balancing immunity, neuroinflammation, and homeostasis.

  2025cites this paper
• Sterile innate immune mechanisms in neurodegenerative diseases

  2025cites this paper
• USP9X suppression attenuates NLRP3 inflammasome activation and ameliorates neuroinflammatory phenotypes with motor function recovery in murine models.

  2025cites this paper
• Gentiopicroside alleviates neuroinflammation in Parkinson's disease by mediating microglial pyroptosis via the NF-κB/NLRP3/GSDMD pathway.

  2025cites this paper
• Beyond the innate immune system: rethinking inflammasomes in multiple sclerosis.

  2025cites this paper
• Sex-specific microRNA regulators of Parkinson’s disease: insights from cohort-stratified simulations of compensatory pathway dynamics

  2025cites this paper
• Treatment of Parkinson's Disease with an Anti-Inflammasome NLRP3 Inhibitor Derived from a Natural Product.

  2025cites this paper
• Pyroptosis; igniting neuropsychiatric disorders from mild depression to aging-related neurodegeneration.

  2025cites this paper
• Mitochondrial translation impairment-triggered neuroinflammation mediates fluoride-induced cognitive deficits.

  2025cites this paper
• Low-dose ciprofol attenuates motor dysfunction in PD mice by inhibiting NLRP3 inflammasome activation.

  2025cites this paper
• Polymeric nanoparticle-mediated GBA1 gene therapy is neuroprotective in a preclinical model of Parkinson’s disease

  2025cites this paper
• Ethanol induces neuroimmune dysregulation and soluble TREM2 generation in a human iPSC neuron, astrocyte, microglia triculture model

  2025cites this paper
• Enhanced neuroprotection in Parkinson's disease by neutrophil-biomimetic nanovesicles through autophagy inhibition and apoptosis antagonism

  2025cites this paper
• Immunity in Parkinson's disease - The role of innate responses.

  2025cites this paper
• Ubiquitination in the Nervous System: From Molecular Mechanisms to Disease Implications

  2025cites this paper
• Methanolic extract of Korean red ginseng attenuates NLRP3 inflammasome-mediated neuroinflammation in chronic cerebral hypoperfusion-induced cognitive impairment: A comparative study.

  2025cites this paper
• Protein regulatory network mediated by palmitoylation modifications in the pathological progression of Parkinson’s disease: a narrative review

  2025cites this paper
• Inflammatory Intracellular Signaling in Neurons Is Influenced by Glial Soluble Factors in iPSC-Based Cell Model of PARK2-Associated Parkinson’s Disease

  2024cites this paper
• The role of inflammasomes in human diseases and their potential as therapeutic targets

  2024cites this paper
• Nanozyme enabled protective therapy for neurological diseases

  2024cites this paper
• Inflammasomes in neurological disorders — mechanisms and therapeutic potential

  2024cites this paper
• What Can Inflammation Tell Us about Therapeutic Strategies for Parkinson’s Disease?

  2024cites this paper
• Role of pyroptosis in the pathogenesis of various neurological diseases.

  2024cites this paper
• Mitochondria Dysfunction and Neuroinflammation in Neurodegeneration: Who Comes First?

  2024cites this paper
• Aiouea padiformis extract exhibits anti-inflammatory effects by inhibiting the ATPase activity of NLRP3

  2024cites this paper
• TXNIP Regulates NLRP3 Inflammasome-Induced Pyroptosis Related to Aging via cAMP/PKA and PI3K/Akt Signaling Pathways

  2024cites this paper
• Manganese accumulation in red blood cells as a biomarker of manganese exposure and neurotoxicity.

  2024cites this paper
• New perspectives on the role of mitochondria in Parkinson’s disease

  2024cites this paper
• Staphylococcus pseudintermedius induces pyroptosis of canine corneal epithelial cells by activating the ROS–NLRP3 signalling pathway

  2024cites this paper
• Necrosis Links Neurodegeneration and Neuroinflammation in Neurodegenerative Disease

  2024cites this paper
• Pyroptosis-mediator GSDMD promotes parkinson's disease pathology via microglial activation and dopaminergic neuronal death.

  2024cites this paper
• Parthanatos: Mechanisms, Modulation, and therapeutic prospects in neurodegenerative disease and stroke.

  2024cites this paper
• Role of NLRP3 in Parkinson's disease: Specific activation especially in dopaminergic neurons

  2024influential citation
• Potential Convergence of Olfactory Dysfunction in Parkinson's Disease and COVID-19: The Role of Neuroinflammation.

  2024cites this paper
• Pellino1 orchestrates gut-kidney axis to perpetuate septic acute kidney injury through activation of STING pathway and NLRP3 inflammasome.

  2024cites this paper
• Microglial- neuronal crosstalk in chronic viral infection through mTOR, SPP1/OPN and inflammasome pathway signaling

  2024cites this paper
• The role of the brain renin-angiotensin system in Parkinson´s disease

  2024cites this paper
• Aberrant Enhanced NLRP3 Inflammasomes and Cell Pyroptosis in the Brains of Prion-Infected Rodent Models Are Largely Associated with the Proliferative Astrocytes

  2024cites this paper
• Microglial SIX2 suppresses lipopolysaccharide (LPS)-induced neuroinflammation by up-regulating FXYD2 expression.

  2024cites this paper
• Inhibiting the IRAK4/NF-κB/NLRP3 signaling pathway can reduce pyroptosis in hippocampal neurons and seizure episodes in epilepsy.

  2024cites this paper
• The NRF2 activator RTA-408 ameliorates chronic alcohol exposure-induced cognitive impairment and NLRP3 inflammasome activation by modulating impaired mitophagy initiation.

  2024cites this paper
• FUBP3 mediates the amyloid-β-induced neuronal NLRP3 expression

  2024cites this paper
• Oridonin exerts anticonvulsant profile and neuroprotective activity in epileptic mice by inhibiting NLRP3-mediated pyroptosis.

  2024cites this paper
• Differential distribution of PINK1 and Parkin in the primate brain implies distinct roles

  2024cites this paper
• Mitochondrial quality control in human health and disease

  2024cites this paper
• Targeting Mitophagy as a Potential Therapeutic Approach for Age‐Related Bone Diseases

  2024cites this paper
• Small extracellular vesicles-derived from 3d cultured human nasal mucosal mesenchymal stem cells during differentiation to dopaminergic progenitors promote neural damage repair via miR-494-3p after manganese exposed mice.

  2024cites this paper
• Eupatorium Lindleyanum DC. Extract Protects against MPTP-induced Mouse of Parkinson’s Disease by Targeting Neuroinflammation

  2024cites this paper
• HucMSCs-derived Exosomes Protect Against 6-hydroxydopamineinduced Parkinson's Disease in Rats by Inhibiting Caspase-3 Expression and Suppressing Apoptosis.

  2024cites this paper